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WO2016127874A1 - Procédé de préparation de sulfate de vorapaxar, et intermédiaire et procédé de préparation associés - Google Patents

Procédé de préparation de sulfate de vorapaxar, et intermédiaire et procédé de préparation associés Download PDF

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Publication number
WO2016127874A1
WO2016127874A1 PCT/CN2016/073241 CN2016073241W WO2016127874A1 WO 2016127874 A1 WO2016127874 A1 WO 2016127874A1 CN 2016073241 W CN2016073241 W CN 2016073241W WO 2016127874 A1 WO2016127874 A1 WO 2016127874A1
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Prior art keywords
preparation
compound
sulfate
reaction
organic solvent
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English (en)
Chinese (zh)
Inventor
蔡茂军
王方道
王猛
王东
周杰
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Chemvon Biotechnology Co Ltd
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Chemvon Biotechnology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/92—Naphthofurans; Hydrogenated naphthofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to a preparation method, an intermediate and an preparation method thereof for an anticoagulant.
  • Vorapaxar is a first-in-class protease-activated receptor 1 (PAR-1) antagonist, an antiplatelet agent designed to reduce platelet aggregation and inhibit the formation of blood clots.
  • PAR-1 protease-activated receptor 1
  • Merck's other new drug for cardiovascular disease, Tredaptive was denied by the FDA. So far, Merck has invested $8 billion to develop vorapaxar, and vorapaxar is now licensed to prevent recurrence of first-time heart disease patients.
  • the original inventors used a one-pot method for the two-step reaction of converting acid 48 to aldehyde 49.
  • the route is long and the yield of the key step is very low.
  • the synthesis method uses the tin-hydrogen reduction acid chloride to prepare the compound 49. In the process, a large amount of thionyl chloride is used, followed by tetrabutyltin hydrogen to obtain the aldehyde 49 under the action of metal palladium. It is not suitable for large-scale industrial production; in addition, since tributyltin hydrogen is a toxic reagent, it has a great toxic effect on the human body and the environment, so it is not suitable for scale-up production.
  • the original inventors converted the acid 14 to the aldehyde 15 by a method of palladium carbon reduction, and the yield reported in the literature was 66%.
  • the yield is very low, only about 10%, while the reaction conditions are harsh, special equipment is needed, the raw materials are expensive, and the post-treatment is cumbersome. Therefore, this method is also not suitable for mass production.
  • the technical problem to be solved by the present invention is to overcome the key steps in the preparation method of the anticoagulant in the prior art.
  • the steps of preparing the fatty carboxylic acid to the fatty aldehyde are cumbersome, the reagents used are toxic, the operation is dangerous, and the environmental pollution is serious.
  • the invention has the advantages of low yield, unsuitable for industrial production and the like, and provides a preparation method, an intermediate and a preparation method thereof for the anticoagulant.
  • the preparation method of the invention has the advantages of simple operation, mild reaction condition, high reaction conversion rate, high yield, high purity of the obtained product, low production cost, simple post-treatment, and is suitable for industrial production.
  • the invention provides a preparation method of Wolpasha Sulfuric Acid Intermediate IV, which comprises the steps of: oxidizing compound III with an oxidizing agent in an organic solvent to obtain Wolpasha Sulfate Intermediate IV;
  • the preparation method of Wolpasha Sulfuric Acid Intermediate IV can be a conventional method of such oxidation reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the organic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; and the chlorinated hydrocarbon solvent is preferably Dichloromethane.
  • the volume-to-mass ratio of the organic solvent to the compound III is preferably from 1 mL/g to 100 mL/g, and more preferably from 5 mL/g to 50 mL/g.
  • the oxidizing agent is preferably a combination of oxalyl chloride and dimethyl sulfoxide, or pyridinium chlorochromate (PCC).
  • the molar ratio of the oxidizing agent to the compound III is preferably from 1 to 6.
  • the oxidizing agent is pyridinium chlorochromate (PCC)
  • the molar ratio of the oxidizing agent to the compound III is more preferably 5 to 6.
  • the oxidizing agent is a combination of oxalyl chloride and dimethyl sulfoxide
  • the molar ratio of the oxalyl chloride to the compound III is further preferably 1-2; the dimethyl sulfoxide and the grass
  • the molar ratio of the acid chloride is preferably from 1 to 3, more preferably from 1 to 2.
  • the temperature of the oxidation reaction is preferably -80 ° C to 40 ° C; when the oxidizing agent is a combination of oxalyl chloride and dimethyl sulfoxide, the The temperature of the oxidation reaction is more preferably -80 ° C to -60 ° C.
  • the temperature of the oxidation reaction is further preferably 0 ° C to 40 ° C, and still more preferably 15 °C ⁇ 30 °C.
  • the progress of the oxidation reaction can be monitored by conventional monitoring methods in the art (for example, TLC, HPLC or NMR), generally in the case of disappearance of Compound III.
  • the time of the oxidation reaction is preferably from 30 minutes to 3 hours.
  • the preparation method of the Wolpasha Sulfuric Acid Intermediate IV is preferably carried out in the presence of a protective gas, and the protection is carried out when the preparation method of the Wolpasha Sulfuric Acid Intermediate IV is carried out in the presence of a protective gas.
  • the gas is preferably one or more of nitrogen, helium, argon, helium, neon, and xenon, and further preferably nitrogen and/or argon.
  • the oxidation reaction when the oxidizing agent is pyridinium chlorochromate (PCC), the oxidation reaction preferably adopts the following steps: a solution of compound III and an organic solvent. It is added dropwise to a mixed solution of pyridinium chlorochromate (PCC) and an organic solvent.
  • PCC pyridinium chlorochromate
  • silica gel is added to the reaction system, and the mass ratio of the silica gel to the pyridinium chlorochromate (PCC) is preferably 2:1 to 1:2, more preferably 1:1 to 1:1.5.
  • the rate of the dropwise addition is based on the temperature of the reaction system not exceeding 30 °C.
  • the oxidation reaction preferably adopts the following post-treatment steps: after the reaction is finished, filtration, washing The mixture was dried and concentrated to obtain purified Woraparva Sulfate Intermediate IV (HPLC purity: 98% or more).
  • the filtration, Washing, drying, and concentrating can employ conventional methods and conditions of operation in the art.
  • the filtration is preferably diatomaceous earth filtered.
  • the washing is preferably carried out by using 1 N hydrochloric acid, water, saturated sodium hydrogencarbonate or saturated brine.
  • the drying is preferably carried out using anhydrous sodium sulfate.
  • the oxidation reaction preferably comprises the following steps: -70 ° C to -80 ° C, A solution of dimethyl sulfoxide and an organic solvent is added dropwise to a solution formed of oxalyl chloride and an organic solvent, and reacted for 30 minutes to 1 hour, and a solution of the compound III and an organic solvent is added dropwise to carry out an oxidation reaction to obtain a sulfuric acid Lapasha intermediate IV.
  • the rate of addition is preferably such that the temperature of the reaction system does not exceed -60 °C.
  • the oxidation reaction preferably includes the following post-treatment step. After the reaction is completed, the reaction is quenched by adding a base, water is added, extracted, washed, and concentrated to give a crude product which is recrystallized to give the purified compound IV.
  • the molar ratio of the base to the compound III is preferably from 3 to 8, more preferably from 4 to 6.
  • the extraction is carried out using a halogenated hydrocarbon solvent, the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; and the chlorinated hydrocarbon solvent is preferably dichloromethane.
  • the recrystallization is preferably carried out by using a mixed solvent of an ester solvent and an alkane solvent, and the ester solvent is preferably ethyl acetate, and the alkane solvent is preferably n-heptan
  • the preparation method of the Wolpasha Sulfuric Acid Intermediate IV further comprises the following steps: in the organic solvent, the compound II and the reducing agent are subjected to a reduction reaction to obtain the compound III; the reducing agent is boron.
  • the reducing agent is boron.
  • the organic solvent may be a conventional organic solvent of the reduction reaction in the art, and an ether solvent and/or an alcohol solvent are particularly preferable in the invention; the ether
  • the solvent is preferably tetrahydrofuran, and the alcohol solvent is preferably n-butanol.
  • the volume-to-mass ratio of the organic solvent to the compound II is preferably 1 mL/g to 100 mL/g, and more preferably 20 mL/g to 50 mL/g.
  • said reducing agent preferably tri (C 1 ⁇ C 4 alkoxy) lithium aluminum hydride, a tri (C 1 ⁇ C 4 alkoxy group), for example, lithium aluminum hydride Lithium trimethoxyaluminum hydride, lithium triethoxyaluminum hydride, lithium tripropoxyaluminum hydride, lithium triisopropoxy aluminum hydride, lithium tributoxyaluminum hydride, lithium triisobutoxyaluminum hydride or tris Lithium tert-butoxyaluminum hydride, preferably lithium tri-tert-butoxyaluminum hydride.
  • lithium aluminum hydride Lithium trimethoxyaluminum hydride, lithium triethoxyaluminum hydride, lithium tripropoxyaluminum hydride, lithium triisopropoxy aluminum hydride, lithium tributoxyaluminum hydride, lithium triisobutoxyaluminum hydride or tris Lithium ter
  • the lithium tris(C 1 -C 4 alkoxy)aluminum hydride may be a commercially available tris(C 1 -C 4 alkoxy)aluminum hydride reagent in the art, or may be passed through aluminum hydride. Lithium is obtained by reacting with 2-3 times the molar amount of a C 1 -C 4 alkyl alcohol.
  • the molar ratio of the reducing agent to the compound II is preferably from 1 to 5, more preferably from 1 to 2.5.
  • the progress of the reduction reaction can be monitored by a conventional monitoring method (for example, TLC, HPLC or NMR) in the art, and generally, when the compound II disappears, the end point of the reaction is
  • a conventional monitoring method for example, TLC, HPLC or NMR
  • the time of the reduction reaction described is preferably from 30 minutes to 3 hours.
  • the preparation method of the compound III is preferably carried out in the presence of a shielding gas.
  • the shielding gas is preferably nitrogen, helium or argon.
  • Compound III The extraction, washing, drying, concentration and recrystallization described can be carried out using conventional methods and conditions of operation in the art.
  • the solvent used for the extraction is preferably an ester solvent, and the ester solvent is preferably ethyl acetate.
  • the washing is preferably washed successively with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine.
  • the solvent used for the recrystallization is preferably a mixed solvent of an ester solvent and an alkane solvent, and the ester solvent is preferably ethyl acetate, and the alkane solvent is preferably n-heptane.
  • the preparation method of the Wolpasha Sulfuric Acid Intermediate IV further comprises the steps of: chlorinating the compound I with a chlorinating reagent in an organic solvent in the presence of a catalyst to obtain the compound II; ;
  • the preparation method of the compound II can adopt a conventional method of chlorination reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention:
  • the organic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; and the chlorinated hydrocarbon solvent is preferably dichloromethane. .
  • the volume-to-mass ratio of the organic solvent to the compound I is preferably 1 mL/g to 100 mL/g, and more preferably 5 mL/g to 30 mL/g.
  • the chlorinating agent is preferably oxalyl chloride.
  • the molar ratio of the chlorinating agent to the compound I is preferably from 1 to 5, more preferably from 2.5 to 3.5.
  • the catalyst is preferably N,N-dimethylformamide.
  • the molar ratio of the catalyst to the compound I is preferably 0.001 to 0.1, more preferably 0.005 to 0.01.
  • the temperature of the chlorination reaction is preferably 20 ° C to 30 ° C.
  • the progress of the chlorination reaction can be monitored by a conventional monitoring method (for example, TLC, HPLC or NMR) in the art, and generally the end point of the reaction is when the compound I disappears.
  • the time of the chlorination reaction is preferably from 30 minutes to 3 hours.
  • the chlorination reaction preferably removes the solvent after completion of the reaction, and the next reaction is carried out without further purification.
  • the preparation method of the intermediate IV of Worapasha Sulfate preferably adopts the following synthetic route:
  • the invention also provides a preparation method of worapacazol sulfate according to formula V, which comprises the steps of: distilling Wolpapar Sulfate intermediate IV with phospholipid VI in an organic solvent in the presence of a base The reaction is carried out to obtain Wolapasha V as shown in Formula V;
  • the preparation method of Worapasha Sulfate as shown in Formula V can be a conventional method of such a Wittig reaction in the art.
  • the following reaction methods and conditions are particularly preferred:
  • the organic solvent is preferably an ether solvent
  • the ether solvent is preferably tetrahydrofuran.
  • the volume-mass ratio of the organic solvent to the Wolpasha Sulfuric Acid Intermediate IV is preferably from 1 mL/g to 100 mL/g. More preferably, it is 10 mL / g - 50 mL / g.
  • the base is preferably an organic base, and the organic base is preferably lithium diisopropylamide (LDA).
  • LDA lithium diisopropylamide
  • the molar ratio of the base to the Wolpasha Sulfuric Acid Intermediate IV is preferably from 1 to 5, more preferably from 3 to 4.
  • the molar ratio of the phospholipid VI to the Wolpasha Sulfuric Acid Intermediate IV is preferably from 1 to 5, further preferably from 2 to 3. .
  • the Woraparva Sulfate Intermediate IV is preferably prepared by the above method
  • the temperature of the Wittig reaction is preferably -20 ° C to -10 ° C.
  • the progress of the Wittig reaction can be monitored by conventional monitoring methods in the art (for example, TLC, HPLC or NMR), generally When the intermediate IV of Worapasha Sulfuric Acid disappears, the time of the reaction is preferably 30 minutes to 4 hours.
  • the preparation method of Wolpasha sulphate as shown in Formula V is preferably carried out in the presence of a protective gas, and the preparation method of Worapasha Sulfate as shown in Formula V is present in the presence of a protective gas.
  • the shielding gas is preferably one or more of nitrogen, helium, argon, helium, neon and xenon, further preferably nitrogen and/or argon.
  • the preparation method of the Worapasha Sulfate as shown in Formula V preferably adopts the following steps: adding the alkali to the solution formed by the phospholipid VI and the organic solvent at -20 ° C to -10 ° C, and reacting 1 to 2 In an hour, a solution of the Wolpaparin intermediate IV and the organic solvent is added dropwise to the above reaction system, and the reaction is carried out for 1 to 2 hours to obtain the above-mentioned Worapasha Sulfate as shown in Formula V.
  • the preparation method of Wolpasha sulphate as shown in Formula V preferably adopts the following post-treatment steps: after the reaction is finished, the reaction is quenched by adding water, hydrochloric acid is adjusted to pH 6-7, extraction, washing, drying, concentration, column chromatography separation Wolapasal sulfate is obtained as shown in Formula V.
  • the extraction, washing, drying, concentration and column chromatography separations may employ conventional methods and conditions of operation in the art.
  • the solvent used for the extraction is preferably an ester solvent, and the ester is dissolved.
  • the agent is preferably ethyl acetate.
  • the washing is preferably washed sequentially with saturated brine.
  • the Worapasha Sulfate as shown in Formula V is preferably prepared by the following route:
  • the invention also provides Compound III, the structure of which is as follows:
  • the invention also provides the preparation method of the compound III, which comprises the steps of: reducing the compound II and the reducing agent in an organic solvent to obtain the compound III;
  • the reducing agent is sodium borohydride or boron
  • the temperature of the reduction reaction is 0-10 ° C;
  • each reaction condition is as described above.
  • the reagents and starting materials used in the present invention are commercially available.
  • the room temperature refers to an ambient temperature of 10 ° C to 35 ° C.
  • the positive progress of the present invention is that the preparation method of the invention has simple operation, mild reaction conditions, high reaction conversion rate, high yield, high purity of the obtained product, low production cost, simple post-treatment, and is suitable for industrial production.
  • the reaction is further stirred at the temperature for 30 minutes, and 170 g of the compound III is dissolved dropwise in 200 mL of a dichloromethane solution, and the mixture is added dropwise.
  • the speed is such that the temperature of the system does not exceed -60 ° C.
  • the stirring reaction was continued at this temperature for 1 hour.
  • the intermediate product 48 (1 g, 3.2 mmol) was dissolved in 20 mL of toluene, 1.25 mL of SOCl 2 was added, and the mixed solution was stirred and heated to 80 ° C, and heating and stirring was continued for 16 hours. The combined solution was concentrated in vacuo and the residue was dissolved in &lt First, 186 mg of Pd(Ph 3 P) 4 was added, followed by dropwise addition of Bu 3 SnH (1.3 ml, 4.8 mmol). The mixed solution was stirred for 3 h, and then subjected to column chromatography to yield 450 mg of intermediate product 49 (yield 48%).
  • a three-necked flask equipped with a stirrer, a thermometer and a nitrogen balloon was prepared, a solution of the crude product 14 (containing 3.1 g of product 14, a volume of about 30 mL) was added, and anhydrous 0.005 mL of DMF was added. After stirring for 5 minutes, 1.22 mL of oxalyl chloride was slowly added dropwise, and the temperature was controlled at 15-25 °C. Stirring was continued for 1 h after the dropwise addition, and the progress of the reaction was monitored by NMR.
  • reaction solution was concentrated to 13.5 mL under vacuum at low temperature ( ⁇ 30 ° C), and the remaining oxalyl chloride was further spun with toluene (31.5 ml ⁇ 2) twice ( ⁇ 50 ° C) to finally obtain 6.8 ml of a solution.
  • the reaction solution was cooled to 15-25 ° C, then 16 mL of THF, 2.2 mL of 2,6-dimethylpyridine.
  • the mass percentage added was 5% Pd/C (0.90 g) (the mass percentage referred to as the mass of palladium as a percentage of the total mass of the palladium carbon reagent), followed by stirring at a temperature of 20 to 25 ° C for 16 h at 100 psiH 2 .
  • the reaction solution was filtered through Celite, washed with a large amount of THF solvent, and then filtered, and then filtered, and the filtrate was filtered again.
  • the combined filtrate was concentrated in vacuo to 31.5 mL at 25 °C.
  • the residual phosphoric acid in the organic phase was washed away with a 2% by mass sodium hydrogen carbonate solution (the mass percentage means the mass of sodium hydrogencarbonate as a percentage of the total mass of the sodium hydrogencarbonate solution), and washed with saline.
  • the solvent was concentrated to 9 ml, 31.5 ml of isopropanol was added, and the mixture was concentrated to 6.8 ml, and the residue was heated to 50 ° C to prepare crystals. 6.8 ml of n-heptane was slowly added and maintained at a temperature of 50 °C. Then slowly cool down (cooling time at least 2.5h) to 25 °C.
  • Comparative Example 3 was prepared by the method of US Pat. No. 6,063,847 A for the preparation of the compound IV of the present invention.
  • the intermediate compound I (3.2 mmol) was dissolved in 20 mL of toluene, 1.25 mL of SOCl 2 was added, and the mixture was stirred and heated to 80 ° C, and heating and stirring was continued for 16 h.
  • the combined solution was concentrated in vacuo and the residue was dissolved in &lt First, 186 mg of Pd(Ph 3 P) 4 was added, followed by dropwise addition of Bu 3 SnH (1.3 ml, 4.8 mmol).
  • the mixed solution was stirred for 3 hours, and then subjected to column chromatography to give 450 mg of Intermediate aldehyde IV (yield: 48%).
  • Comparative Example 4 was prepared using the method of the patent (WO2006/076564A1 or PCT/US2006/001208) to prepare the compound IV of the present invention.
  • a three-necked flask equipped with a stirrer, a thermometer and a nitrogen balloon was prepared, and a solution of the crude intermediate compound I (containing 31 g of the intermediate compound I in a volume of about 300 ml) was added, and anhydrous 0.05 mL of DMF was added. After stirring for 5 minutes, 12.2 mL of oxalyl chloride was slowly added dropwise, and the temperature was controlled at 15-25 °C. Stirring was continued for 1 h after the dropwise addition, and the progress of the reaction was monitored by NMR.
  • reaction solution was concentrated to 135 ml under vacuum at low temperature ( ⁇ 30 ° C), and the remaining oxalyl chloride was further spun with toluene (315 ml ⁇ 2) twice ( ⁇ 50 ° C) to finally obtain 68 ml of a solution.
  • the reaction solution was cooled to 15-25 ° C, then 160 mL of THF and 22 mL of 2,6-dimethylpyridine. 5% Pd/C (9.0 g) was added, followed by 100 psi H 2 , and the temperature was stirred at 20-25 ° C for 16 h.
  • reaction solution was filtered through Celite, washed with a large portion of THF solvent and a solid catalyst, and filtered again.
  • the combined filtrate was concentrated in vacuo to 315 mL at 25 °C.
  • 158 mL of MTBE and 158 mL of 10% aqueous phosphoric acid solution were added to remove 2,6-lutidine, and the temperature was controlled at 10 °C.
  • the residual phosphoric acid in the organic phase was washed with a 2% sodium hydrogen carbonate solution and washed with brine.
  • solvent was concentrated to 90 mL, 315 mL of isopropyl alcohol was added, concentrated to 68 ml, and the residue was heated to 50 ° C to prepare crystals.
  • n-heptane 68 mL of n-heptane was slowly added and maintained at a temperature of 50 °C. Then slowly cool down (cooling time at least 2.5h) to 25 °C. Further, 34 ml of n-heptane was slowly added to a temperature of 25 ° C, and then further cooled to 20 ° C and allowed to stand for at least 20 h. Filtration, washing (25% by volume of a mixed solvent of isopropanol and n-heptane, the volume percentage is the ratio of the volume of isopropanol to the mixed solvent volume of isopropanol and n-heptane), obtained after drying 3.5 g of intermediate aldehyde compound IV (yield 11%).

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation d'un anticoagulant, et un intermédiaire et un procédé de préparation associés. L'invention concerne un procédé de préparation d'un intermédiaire IV de sulfate de vorapaxar, qui comprend les étapes suivantes : dans un solvant organique, effectuer une réaction d'oxydation sur le composé III et un oxydant, de façon à obtenir l'intermédiaire IV du sulfate de vorapaxar. Le procédé de préparation de la présente invention présente un fonctionnement simple, des conditions de réaction douces, un taux de conversion de réaction élevée et un rendement élevé ; et le produit préparé possède une pureté élevée, un faible coût de production, un post-traitement simple, et est approprié pour une production industrielle.
PCT/CN2016/073241 2015-02-13 2016-02-03 Procédé de préparation de sulfate de vorapaxar, et intermédiaire et procédé de préparation associés Ceased WO2016127874A1 (fr)

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CN201510079004.8 2015-02-13
CN201510079004.8A CN105985303B (zh) 2015-02-13 2015-02-13 抗凝血剂的制备方法、中间体及其制备方法

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CN115124578A (zh) * 2021-03-29 2022-09-30 上海医药工业研究院 一种络塞维中间体、其制备方法和用途
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CN113929612A (zh) * 2020-06-29 2022-01-14 鲁南制药集团股份有限公司 一种依托度酸中间体的制备方法
CN113929612B (zh) * 2020-06-29 2024-05-14 鲁南制药集团股份有限公司 一种依托度酸中间体的制备方法
CN115124578A (zh) * 2021-03-29 2022-09-30 上海医药工业研究院 一种络塞维中间体、其制备方法和用途
CN115124578B (zh) * 2021-03-29 2024-05-10 上海医药工业研究院 一种络塞维中间体、其制备方法和用途
CN116041347A (zh) * 2023-01-12 2023-05-02 上海新礼泰药业有限公司 非奈利酮中间体的制备方法

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